Multinational Randomized Clinical Trial Research Articles

Clinical Characteristics, Treatment, and Outcomes of Provoked Acute Cerebral Sinovenous Thrombosis in Patients

Background Cerebral sinus venous thrombosis (CSVT) is a rare pediatric condition with an estimated incidence of 0.7 per 100,000 children. However, amongst pediatric venous thromboembolism (VTE), the proportion of CSVT is high, at about 10% of all pediatric VTE. Key risk factors include perinatal stressors in cases of neonatal CSVT and acute infections, especially head and neck infections, in older children. To date, few multinational trials of pediatric VTE treatment have reported findings specifically among CSVT patients. Aims We sought to describe the clinical characteristics, treatment strategies, and outcomes of the patients with provoked acute CSVT enrolled in the Kids-DOTT trial and to compare these features to those of Kids-DOTT participants with non-CSVT VTE. Methods Kids-DOTT was an NIH-sponsored multinational randomized clinical trial (RCT) comparing 6 weeks vs. 3 months of anticoagulation for provoked acute VTE treatment in patients <21 years, with two non-randomized cohort arms run in parallel to the RCT for patients with persistent antiphospholipid antibodies or complete veno-occlusion at 6 weeks post-diagnosis of the index VTE. The primary RCT findings were recently published. In the present analysis, descriptive statistics were used to summarize patient and thrombus characteristics, treatments, and outcomes, and variables were compared between CSVT and non-CSVT VTE groups using Mann-Whitney U test for continuous variables and Chi-squared or Fisher's exact test, as appropriate, for categorical variables. All statistical analyses were performed using R Core Team, 2021. A P-value of <0.05 was considered statistically significant. Results Among 532 patients enrolled in the Kids-DOTT trial, the index VTE was a CSVT in 75 (14%). Age distribution differed significantly ( P=0.002) between CSVT and non-CSVT VTE patients, with the CSVT more likely to occur in neonates and children, compared to non-CSVT VTE more likely to occur in adolescents. CSVT was less likely to be CVC-related compared to non-CSVT VTE. The frequency of any infection (56.9% vs 26%, p<0.001) and specifically infection of the head/neck (35.4% vs 2%; P<0.001) as a provoking factor was significantly higher for CSVT vs. non-CSVT VTE. Non-head and neck infections were less likely to be associated with CSVT compared to non-CSVT VTE. One-third of CSVT patients received 6 weeks, while two-thirds received > 3 months, of anticoagulation (Table 2). No patients developed ISTH-defined symptomatic recurrent VTE or clinically relevant bleeding. Conclusions These multinational trial findings substantiate those of retrospective studies implicating head/neck infection as an important provoking factor for CSVT in young patients. The absence of recurrent VTE or clinically relevant bleeding among CSVT patients managed with anticoagulation in Kids-DOTT serve to augment recent RCT findings of CSVT treatment in children involving direct oral anticoagulants, demonstrating the safety and efficacy of therapeutic anticoagulation for pediatric CSVT.

RWD18 Age Comparisons across Real-World Evidence Research, Randomized Clinical Trials, and Surveillance, Epidemiology, and End Results (SEER) in Advanced Cancer

We compared ages of patients with advanced melanoma, breast, lung, liver, or kidney cancer in recently completed real-world evidence (RWE) chart review studies, multinational randomized clinical trials (RCTs) upon which the RWE studies were based, and the most recently available Surveillance, Epidemiology, and End Results (SEER) data.

Efficacy and safety of Kras inhibitors in pancreatic cancer: A systematic review of clinical trials.

e16297 Background: Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive tumor and is one of the leading causes of cancer related deaths worldwide. Kirsten Rat Sarcoma (KRAS)mutation resulting in tumor cell proliferation and cancer progression is a frequently mutated oncogene in various cancers and is approximately seen in 90% of pancreatic ductal adenocarcinoma. Efforts are being done to target Kras mutation in the last 3–4 decades. Here in, we report the results of the systemic review of clinical trials done on chemotherapeutic agents targeting Kras mutated pancreatic cancer. Methods: We followed PRISMA guidelines to conduct this systematic review. A literature search was performed on PubMed, Clinicaltrials.gov, and Embase with mesh terms, “pancreatic neoplasm’’ and “kras” from the inception of data till 01/05/2023. We screened 4191 articles and included 3 clinical trials with published study results and 3 ongoing clinical trials. Results: In this systematic review, data on 2 chemotherapeutic agents Sotorasib (AMG510) and Adagrasib (MRTX849) which are Kras G12C inhibitors, are obtained from Code Break-100 and preliminary results of KRYSTAL-1 clinical trials, respectively. In these 2 clinical trials (N-48), all the patients had advanced pancreatic cancer with Kras G12C mutation and were previously treated with chemotherapy. 10 patients in Krystal-1 trial, who received adagrasib showed progression-free survival (PFS) of 6.6 months, disease control rate (DCR) of 100 % and partial response (PR) of 50%. 38 patients in the Code Break-100 trial, who received Sotorasib showed PFS of 4 months, DCR of 84.2% and PR of 21.1%. However, 50% of patients in the KRYSTAL-1 trial are still receiving treatment. Grade 3 /4 adverse events were seen in 21% and 16% of patients in the KRYSTAL-1 and Code Break-100 trial, respectively. Other Kras G12C inhibitors like D-1553, Sotorasib in combination with 2nd line chemotherapy are under investigation. Results of a clinical trial on anti KrasG12D siRNA done on locally advanced pancreatic cancer patients showed a median overall survival of 15.12 months with no dose limiting adverse events. A multinational randomized phase 2b clinical trial is ongoing for the evaluation of efficacy of siRNA based drug in combination with chemotherapy. Conclusions: Both Adagrasib and Sotorasib showed promising results in the pretreated Kras G12C pancreatic cancer patients with acceptable safety profile. Further exploration of these drugs and their combination with other chemotherapeutic agents is necessary. [Table: see text]

Physician-Reported Experience and Usability of the MyPal Platform: A Palliative Care Digital Health Intervention.

There is a lack of research focusing on the physician-end, their experiences, and their perception of usability with an eHealth intervention. The aim of this study was to evaluate physician satisfaction, and perception of usability following the use of the MyPal platform, a digital health intervention to foster palliative care for hematological cancer patients. Participants were healthcare professionals active in the project's multinational randomized clinical trial evaluating the impact of the MyPal platform. A post-study electronic questionnaire was administered comprised of; 2 standardized questionnaires (PSSUQ, UEQ) and a feature satisfaction questionnaire, and an open ended question. All questionnaire scores were relatively high and the platform was more than marginally accepted by all participants.

Association of Surgical Margin Distance With Survival in Patients With Resected Head and Neck Squamous Cell Carcinoma

Clear surgical margins reduce the risk of local recurrence, improve survival, and determine decision-making with regard to adjuvant treatment of squamous cell carcinoma of the head and neck (SCCHN). However, the definitions of clear, close, or positive surgical margins vary in both the literature and in practice. To examine whether the association between surgical margin distance and survival varies by primary tumor site. This was a secondary analysis of a multi-institutional, multinational randomized clinical trial. The trial enrolled patients from January 22, 2007, to March 29, 2013, with stage II to IVA resected SCCHN with extranodal extension (ENE) or positive margins (<5 mm from invasive tumor to the resected margin). The current analysis included those patients with known ENE and margin status and was conducted from April 29, 2022, to December 19, 2022. Patients received adjuvant chemoradiotherapy plus either placebo or lapatinib. Overall survival (OS) was calculated to examine association with surgical margin distance, primary site, and survival, with stratification by ENE status. Among 688 patients enrolled in the trial, 630 patients with known ENE and margin status were included. Exact patient ages were not made available; 523 (83%) patients were male, and 415 (66%) patients were White. Patients with 1 high-risk feature (positive margins or ENE) had significantly better OS vs 2 high-risk features (hazard ratio [HR], 0.65; 95% CI, 0.49-0.87), although most other results were not statistically significant. For example, in the cohort with ENE-negative disease, multivariable adjusted analysis showed nonsignificant improvements with shorter surgical margin distance (1- to 5-mm margins), and no association with OS was found in the cohort with ENE-positive status (either >5 mm margins or 1-5 mm margins). The association between survival and margin distance varied based on primary site, human papillomavirus (HPV) status, and ENE status. For example, HPV-positive status was associated with a significant and clinically meaningful increase in survival (adjusted HR, 0.33; 95% CI, 0.11-0.97). The improvement was greatest, although not significantly so, in patients with ENE- and HPV-negative oropharynx (OP), hypopharynx (HP), and larynx cancer (HR, 0.57; 95% CI, 0.30-1.10). No survival benefit was seen in ENE-negative oral cavity cancer (HR, 0.89; 95% CI, 0.45-1.77), nor was an association observed between margins and OS in HPV-positive OP cancer. In this secondary analysis of a randomized clinical trial, the presence of high-risk features (extranodal extension, positive margins, or both) was associated with worse survival; longer survival was observed with greater surgical margin distance among patients with oral cavity tumors and human papillomavirus-negative tumors of the OP, larynx, or HP. No other significant differences were found. These findings support variable interpretation of surgical margin distance based on the primary site and HPV status. ClinicalTrials.gov Identifier: NCT00424255.

Predicting Treatment Response with Sensory Phenotyping in Post-Traumatic Neuropathic Pain.

Currently available treatments for neuropathic pain are only modestly efficacious when assessed in randomized clinical trials and work for only some patients in the clinic. Induced-pain or gain-of-function phenotypes have been shown to predict response to analgesics (vs placebos) in patients with neuropathic pain. However, the predictive value of these phenotypes has never been studied in post-traumatic neuropathic pain. Mixed-effects models for repeated measures were used to evaluate the efficacy of pregabalin vs placebo in subgroups with induced-pain phenotypes (i.e., hyperalgesia or allodynia) in data from a recent, multinational randomized clinical trial (N = 539) that identified phenotypic subgroups through the use of a structured clinical exam. The difference in mean pain score between the active and placebo groups (i.e., delta) after 15 weeks of treatment for the subgroup with hyperalgesia was -0.76 (P = 0.001), compared with 0.19 (P = 0.47) for the subgroup that did not have hyperalgesia. The treatment-by-phenotype interaction, which tests whether subgroups have statistically different treatment responses, was significant (P = 0.0067). The delta for the subgroup with allodynia was -0.31 (P = 0.22), compared with -0.30 (P = 0.22) for the subgroup that did not have allodynia (treatment-by-phenotype interaction P = 0.98). These data suggest that hyperalgesia, but not allodynia, predicts response to pregabalin in patients with chronic post-traumatic neuropathic pain. This study extends the growing data supporting the utility of induced-pain phenotypes to predict response to analgesics in post-traumatic neuropathic pain. Sensory phenotyping in large, multisite trials through the use of a structured clinical exam has the potential to accelerate the development of new analgesics and improve the generalizability of clinical trial results.

Evaluation of the Age, Biomarkers, and Clinical History–Bleeding Risk Score in Patients With Atrial Fibrillation With Combined Aspirin and Anticoagulation Therapy Enrolled in the ARISTOTLE and RE-LY Trials

Most patients with atrial fibrillation (AF) and coronary artery disease have indications for preventing stroke with oral anticoagulation therapy and preventing myocardial infarction and stent thrombosis with platelet inhibition. To evaluate whether the recently developed ABC (age, biomarkers, and clinical history)-bleeding risk score might be useful to identify patients with AF with different risks of bleeding during concomitant aspirin and anticoagulation therapy. The biomarkers in the ABC-bleeding risk score (growth differentiation factor 15, hemoglobin, and troponin) were measured in blood samples collected at randomization between 2006 and 2010 in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial and between 2005 and 2009 in the RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial, both of which were multinational randomized clinical trials. The trials were reported 2011 and 2009, respectively. A total of 24 349 patients with AF (14 980 patients from the ARISTOTLE trial and 9369 patients from the RE-LY trial) were analyzed in the present cohort study. The median (interquartile range) length of follow-up was 1.8 (1.3-2.3) years in the ARISTOTLE cohort and 2.0 (1.6-2.3) years in the RE-LY cohort. Data analysis was performed from February 2018 to June 2019. Concomitant aspirin treatment during study follow-up. Time to first occurrence of a major bleeding was determined according to International Society on Thrombosis and Hemostasis definition. Hazard ratios were estimated with Cox models adjusted for ABC-bleeding risk score and randomized treatment. The median (interquartile range) age was 70 (63-76) years in the ARISTOTLE cohort and 72 (67-77) years in the RE-LY cohort (5238 patients [35.6%] in the ARISTOTLE cohort and 3086 patients [36.4%] in the RE-LY cohort were women). The total number of patients with a first major bleeding event was 651 (207 with aspirin and 444 without) in ARISTOTLE and 463 (238 with aspirin and 225 without) in RE-LY. For both cohorts, in those with a low ABC-bleeding risk score, the absolute bleeding rate was low even with concomitant aspirin treatment, whereas in those with a higher ABC-bleeding risk score, the rate of bleeding was higher with concomitant aspirin compared with oral anticoagulation alone (ARISTOTLE, hazard ratio, 1.65; 95% CI, 1.40-1.95; P < .001; RE-LY, hazard ratio, 1.70; 95% CI, 1.42-2.04; P < .001). Thus, a low annual ABC-bleeding risk (eg, 0.5% without aspirin use) would with concomitant aspirin result in an annual rate of 0.8%, and a high estimated ABC-bleeding risk (eg, 3.0%) would result in a substantially higher rate of 5.0%. These findings suggest that the ABC-bleeding risk score identifies patients with different risks of bleeding when combining aspirin and oral anticoagulation. The ABC-bleeding risk score may, therefore, be a useful tool for decision support concerning intensity and duration of combination antithrombotic treatment in patients with AF and coronary artery disease.

Aesthetic assessment after root coverage of multiple adjacent recessions with coronally advanced flap with adjunctive collagen matrix or connective tissue graft: Randomized clinical trial.

Few studies have looked at professional assessment or patient perception of aesthetics after root coverage procedures. The addition of connective tissue grafts (CTG) seems to improve aesthetic outcomes. The objective of this a priori analysis was to compare aesthetics after addition of CTG or a collagen matrix (CMX) to coronally advanced flap (CAF). Two independent, trained and calibrated assessors analysed baseline and 6-month post-operative Images from 183 subjects with 475 recessions from a previously reported multicentre multinational randomized clinical trial. Theroot coverage aesthetic score (RES) was assessed in its five constituent components after assessing the suitability of images blindly with regard to treatment assignment and centre. Data were analysed at the tooth and subject level. One hundred and fifty-five subjects (81 CTG) and 393 teeth (207 CTG) were included in the analysis. CTG control subjects had higher total RES scores (mean adjusted difference of 1.3±0.8 RES units, p=0.002). Analyses of RES subcomponents showed that the CTG group had higher scores in terms of gingival margin position but that better marginal tissue contour (OR 3.0, 95% CI 1.2-7.7) and soft tissue texture (OR 3.3, 95% CI 1.9-5.8) was observed for the CMX group. No significant differences were observed for mucogingival alignment and gingival colour. Better overall RES scores were observed for the CTG group. Better marginal tissue texture and marginal contour were observed in the CMX group. More research and development is needed to optimize materials to be used in conjunction with CAF to improve root coverage without negatively affecting tissue texture and marginal contour.

Clinical trials involving carbon-ion radiation therapy and the path forward.

To describe the international landscape of clinical trials in carbon-ion radiotherapy (CIRT), the authors reviewed the current status of 63 ongoing clinical trials (median, 47 participants) involving CIRT identified from the US clinicaltrials.gov trial registry and the World Health Organization International Clinical Trials Platform Registry. The objectives were to evaluate the potential for these trials to define the role of this modality in the treatment of specific cancer types and identify the major challenges and opportunities to advance this technology. A significant body of literature suggested the potential for advantageous dose distributions and, in preclinical biologic studies, the enhanced effectiveness for CIRT compared with photons and protons. In addition, clinical evidence from phase I/II trials, although limited, indicated the potential for CIRT to improve cancer outcomes. However, current high-level phase III randomized clinical trial evidence does not exist. Although there has been an increase in the number of trials investigating CIRT since 2010, and the number of countries and sites offering CIRT is slowly growing, this progress has excluded other countries. Several recommendations are proposed to study this modality to accelerate progress in the field, including: 1) increasing the number of multinational randomized clinical trials, 2) leveraging the existing CIRT facilities to launch larger multinational trials directed at common cancers combined with high-level quality assurance; and 3) developing more compact and less expensive next-generation treatment systems integrated with radiobiologic research and preclinical testing.

Economic Analysis of Apixaban Therapy for Patients With Atrial Fibrillation From a US Perspective

The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial reported that apixaban therapy was superior to warfarin therapy in preventing stroke and all-cause death while causing significantly fewer major bleeds. To establish the value proposition of substituting apixiban therapy for warfarin therapy in patients with atrial fibrillation, we performed a cost-effectiveness analysis using patient-level data from the ARISTOTLE trial. To assess the cost and cost-effectiveness of apixaban therapy compared with warfarin therapy in patients with atrial fibrillation from the perspective of the US health care system. This economic analysis uses patient-level resource use and clinical data collected in the ARISTOTLE trial, a multinational randomized clinical trial that observed 18 201 patients (3417 US patients) for a median of 1.8 years between 2006 and 2011. Apixaban therapy vs warfarin therapy. Within-trial resource use and cost were compared between treatments, using externally derived US cost weights. Life expectancies for US patients were estimated according to their baseline risk and treatment using time-based and age-based survival models developed using the overall ARISTOTLE population. Quality-of-life adjustment factors were obtained from external sources. Cost-effectiveness (incremental cost per quality-adjusted life-year gained) was evaluated from a US perspective, and extensive sensitivity analyses were performed. Of the 3417 US patients enrolled in ARISTOTLE, the mean (SD) age was 71 (10) years; 2329 (68.2%) were male and 3264 (95.5%) were white. After 2 years of anticoagulation therapy, health care costs (excluding the study drug) of patients treated with apixaban therapy and warfarin therapy were not statistically different (difference, -$60; 95% CI, -$2728 to $2608). Life expectancy, modeled from ARISTOTLE outcomes, was significantly longer with apixaban therapy vs warfarin therapy (7.94 vs 7.54 quality-adjusted life years). The incremental cost, including cost of anticoagulant and monitoring, of achieving these benefits was within accepted US norms ($53 925 per quality-adjusted life year, with 98% likelihood of meeting a $100 000 willingness-to-pay threshold). Results were generally consistent when model assumptions were varied, with lifetime cost-effectiveness most affected by the price of apixaban and the time horizon. Apixaban therapy for ARISTOTLE-eligible patients with atrial fibrillation provides clinical benefits at an incremental cost that represents reasonable value for money judged using US benchmarks for cost-effectiveness. clinicaltrials.gov Identifier: NCT00412984.

Stroke : Highlights of Selected Articles

<i>Stroke</i> : Highlights of Selected Articles

Differences in antiretroviral safety and efficacy by sex in a multinational randomized clinical trial

Background and objective:Worldwide, 50% of human immunodeficiency virus (HIV)-infected people are women. This study was to evaluate whether the safety and efficacy outcomes of three initial antiretroviral regimens (ARVs) differed by sex.Methods:Antiretroviral regimen naive participants from nine countries in four continents were assigned to ARVs with efavirenz (EFV) plus lamivudine–zidovudine, atazanavir (ATV) plus didanosine (ddI)-EC/emtricitabine (FTC) or EFV plus FTC–tenofovir–DF. The primary objective was to estimate the sex difference on efficacy outcome of treatment failure defined as one of the following: 1. Time to 1st of confirmed virologic failure, 2. WHO Stage 4 progression or 3. death with hazard ratio (HR) and 95% confidence interval (CI) from adjusted Cox regression models.Results:In all, 739 (47%) women and 832 (53%) men with HIV were evaluated. Women had higher pretreatment CD4+(182 vs 165 cells/mm3; P < 0.001) and lower HIV-1 RNA (4.9 log10 vs 5.2 log10 copies/ml; P < 0.001) compared to men. Association of sex with time to regimen failure differed by treatment arm (P = 0.018). For atazanavir plus didanosine-EC plus emtricitabine, women had a longer time to treatment failure compared to men [adjusted HR (aHR) = 0.59; 95% CI 0.40–0.87]. Women were less likely to prematurely discontinue treatment prematurely (aHR = 0.74; 95% CI 0.56–0.98). Women assigned to efavirenz plus lamivudine–zidovudine were more likely to have a primary safety event compared to men (aHR = 1.49; 95% CI 1.18–1.88).Conclusion:Antiretroviral efficacy and safety differed by sex in this study. Consideration of potential effects of sex on antiretroviral outcomes is important for the design of future clinical trials and for HIV treatment guidelines.

Efficacy and safety of linagliptin as monotherapy or add-on treatment in Asian patients with suboptimal glycemic control: a pooled analysis

Aims:To evaluate the efficacy and safety of the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin in Asian patients with type 2 diabetes mellitus (T2DM), a rapidly increasing population.Methods:Data were pooled for Asian patients receiving linagliptin orally once daily, as monotherapy or added to existing oral antidiabetes therapies, in multinational randomized placebo-controlled clinical trials. Efficacy data were taken from four pivotal trials with 24-week durations to allow for robust efficacy assessment. Safety data were pooled from a wider group of 10 trials with varying durations to capture the largest possible incidence of adverse events (AEs). The primary efficacy endpoint was change from baseline to week 24 in HbA1c. AEs were analyzed descriptively.Results:Mean baseline HbA1c (±SD) in this population was 8.2 ± 0.9%. Placebo-corrected mean change in HbA1c after 24 weeks was −0.79% (95% confidence interval [CI]: −0.92 to −0.67; p < 0.0001). Placebo-corrected mean change in fasting plasma glucose was −17.8 ± 2.4 mg/dL (95% CI: −22.6, −13.0; p < 0.0001). In a small subgroup, mean post-prandial glucose was reduced by a placebo-corrected −56.9 ± 14.0 mg/dL (95% CI: −85.2, −28.5). AEs occurred in 58.0% of linagliptin patients (serious AEs in 2.4%) and 58.2% of placebo patients (serious AEs in 3.0%).Conclusions:This study was limited by the post hoc nature of the analysis, and because the pooling did not differentiate between geographically distant Asian regions. Nonetheless, this analysis provides evidence that linagliptin was efficacious and well tolerated as monotherapy or added to other oral antidiabetes therapies in Asian patients with T2DM.

Assessing the Cost Effectiveness of Pre-Exposure Prophylaxis for HIV Prevention in the US

About 50,000 people are infected with HIV in the US each year and this number has remained virtually the same for the past decade. Yet, in the last few years, evidence from several multinational randomized clinical trials has shown that the provision of antiretroviral drug to uninfected persons (i.e. pre-exposure prophylaxis) reduces the incidence of HIV by about 50%. However, evidence from cost-effectiveness studies conducted in the US yield widely varying estimates of the cost per quality-adjusted life-year (QALY) gained, and this variation reflects the substantial uncertainty surrounding the determinants of HIV transmission (e.g. adherence rates to prophylactic medications, the average number of sexual partners, the number and types of sexual acts, the viral load of infected partners, and the proportion of contacts where condoms are used), as well as different approaches to translating a reduction in HIV cases into an estimate of the increase in the number of QALYs.

Implementation fidelity of Multidimensional Family Therapy in an international trial

Implementation fidelity, a critical aspect of clinical trials research that establishes adequate delivery of the treatment as prescribed in treatment manuals and protocols, is also essential to the successful implementation of effective programs into new practice settings. Although infrequently studied in the drug abuse field, stronger implementation fidelity has been linked to better outcomes in practice but appears to be more difficult to achieve with greater distance from model developers. In the INternational CAnnabis Need for Treatment (INCANT) multi-national randomized clinical trial, investigators tested the effectiveness of Multidimensional Family Therapy (MDFT) in comparison to individual psychotherapy (IP) in Brussels, Berlin, Paris, The Hague, and Geneva with 450 adolescents with a cannabis use disorder and their parents. This study reports on the implementation fidelity of MDFT across these five Western European sites in terms of treatment adherence, dose and program differentiation, and discusses possible implications for international implementation efforts.

Missed OPPORTUNITY: growth hormone therapy in adults with CKD

The results of the largest, double-blind, placebo-controlled, multicentre, multinational randomized clinical trial (RCT) evaluating the effects of human growth hormone (hGH) on clinical outcome in 695 haemodialysed adults are published in this issue [1]. Designed to answer the important question whether hGH therapy might improve the notoriously poor survival in patients on dialysis, the OPPORTUNITY trial will enter the collective memory of the nephrology community as a paradigmatic case illustrating the unfortunate dependence of clinical pharmacological research on the short-term interest of industry sponsors.

Abstract A97: Final phase 1/2a results evaluating the cyclodextrin-containing nanoparticle CRLX101 in patients with advanced solid tumor malignancies.

Abstract Introduction: Topoisomerase-1-inhibiting camptothecin (CPT) and derivatives such as irinotecan (CPT-11) and topotecan demonstrate clinical utility across multiple cancer types. Use of these agents remains limited by insufficient tumor exposure and high systemic toxicity. A novel cyclodextrin-containing polymer conjugate of CPT that self-assembles into nanoparticles, CRLX101 delivers sustained levels of active CPT into cancer cells while substantially reducing systemic exposure. In vitro and in vivo data suggest superior activity of CRLX101 in multiple tumor models. Efforts are made now to demonstrate the safety and efficacy of CRLX101 in human patients with advanced solid tumor malignancies. Experimental Procedures: CRLX101 was administered intravenously over 1 hour every other week (EOW) to patients (pts.) with advanced and multiply pre-treated solid tumor malignancies. In phase 1, 24 pts. received CRLX101 at 5 escalating dose levels. Following identification of a maximum tolerated dose (MTD), a 38 patient phase 2a MTD-expansion cohort was enrolled at 3 clinical sites. Summary of Data: As of a data cut-off of 6/1/11, 62 total pts. (31 F; 31 M) received CRLX101 at doses ranging from 6 mg/m2 to 18 mg/m2 of CPT equivalent per dose. In phase 1, 2 pts. (18 mg/m2) experienced dose limiting toxicity of CTCAE v3.0 grade (G)4 thrombocytopenia with one of these pts. additionally experiencing G4 neutropenia. An MTD/recommended phase 2 dose (RP2D) of CRLX101 was established at 15 mg/m2 EOW. Among 44 phase 1 or 2a pts. receiving the MTD/RP2D, most common grade 3/4 adverse events considered by investigators to be at least possibly related to study drug included neutropenia (9 events observed among 6 pts.) and lymphopenia (3 events observed among 2 pts.). Phase 2a pts. received CRLX101 for periods of time ranging from 1 day to approximately 13 months (mos.) with an average duration of 3.3 mos. Among 36 evaluable phase 2a pts. receiving the MTD, mean plasma Cmax and AUCall were 306 μg./L. and 27.1 mg./L.*hr. (polymer-unconjugated) and 8260 μg./L. and 300 mg./L.*hr. (polymer-conjugated), respectively. Mean urinary clearance of polymer-conjugated and free CPT over the 0–8 hr., 8–24 hr., and 24–48 hr. collection intervals post CRLX101 dosing were 0.0299, 0.0074, and 0.0062 L./hr. (polymer-conjugated) and 0.0888, 0.0898, and 0.1010 L./hr. (free CPT), respectively. Among all phase 2a pts., overall median progression-free survival (mPFS) was 3.7 mos., with mPFS of 4.4 mos. observed among 21 NSCLC pts. (4.8 mos. excluding 6/21 pts. with squamous cell histology). At time of data cut-off, 6 pts. (incl. 3 NSCLC pts.) remain on therapy. Notably, of the 21 NSCLC pts. in phase 2a (with an average of 3 prior regimens of chemotherapy), 66.7% (14/21) achieved stable disease (SD) ≥ 3 mos. and 14.3% (3/21) achieved SD ≥ 6 mos. Conclusions: CRLX101 appears to be extremely well tolerated with an MTD/RP2D of 15 mg/m2 EOW. Pharmacokinetics are linear and suggest prolonged duration of CPT tumor exposure. Similarly, extended periods of stable disease observed across multiple tumor types are encouraging and merit further investigation. Patients are currently being enrolled into a multinational randomized clinical trial in 2nd/3rd line NSCLC and additional studies in renal cell cancer, small-cell lung cancer, ovarian cancer, and gastric cancer are being developed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A97.

Cost-effectiveness analysis of antimuscarinics in the treatment of patients with overactive bladder in Spain: A decision-tree model

BackgroundFesoterodine, a new once daily antimuscarinic, has proven to be an effective, safe, and well-tolerated treatment in patients with overactive bladder (OAB). To date, no analysis has evaluated the economic costs and benefits associated with fesoterodine, compared to antimuscarinics in Spain. The purpose of this analysis was to assess the economic value of OAB treatment with fesoterodine relative to extended release tolterodine and solifenacin, from the societal perspective.MethodsThe economic model was based on data from two 12-week, randomized, double-blind, and multicenter trials comparing fesoterodine and tolterodine extended released (ER). Treatment response rates for solifenacin were extracted from the published literature. Discontinuation and efficacy were based on the results of a 12-week multinational randomized clinical trial extrapolated to 52 weeks. Changes in health related quality of life were assessed with the King's Health Questionnaire, which was transformed into preference-based utility values. Medical costs included (expressed in € 2010) were antimuscarinics, physician visits, laboratory tests, incontinence pads and the costs of OAB-related comorbidities, fractures, skin infections, urinary tract infections, depression, and nursing home admissions associated with incontinence. Time lost from work was also considered. Univariate sensitivity analyses were also performed.ResultsAt week 12, continents accounted for 50.6%, 40.6% and 47.2% of patients in the fesoterodine, tolterodine, and solifenacin groups, respectively. By week 52, the projected proportions of patients remaining on therapy were 33.1%, 26.5% and 30.8%, respectively. The projected quality- adjusted life years (QALY) gain (compared to baseline) over the 52-week simulation period were 0.01014, 0.00846 and 0.00957, respectively. The overall treatment cost was estimated at €1,937, €2,089 and €1,960 for fesoterodine, tolterodine and solifenacin, respectively. Therefore, treatment with fesoterodine resulted in similar overall costs and greater QALY gain than treatment with either tolterodine or solifenacin. Sensitivity analysis showed that these results were robust to all changes performed.ConclusionsThe results of this economic analysis suggest that fesoterodine is a cost-effective alternative to tolterodine and solifenacin for the treatment of patients with OAB in Spain. Fesoterodine provides additional health benefits while maintain a similar level of costs being a cost-effective treatment strategy from a societal perspective.

Bayesian Modelling of Healthcare Resource Use in Multinational Randomized Clinical Trials

Most cost-effectiveness analyses conducted alongside multinational randomized clinical trials (RCT) are carried out applying the unit costs from the country of interest to trial-wide resource use items with the objective of estimating total healthcare costs by treatment group. However, this approach could confound 'price effects' with 'country effects'. An alternative approach is to use multilevel modelling techniques to analyse healthcare resource use (HCRU) from the trial, and obtain country-specific total costs by applying country-specific unit costs to corresponding shrinkage estimates of differential HCRU. To illustrate the feasibility of this approach, we analysed data from twin multinational RCTs, which enrolled approximately 2000 individuals into three treatment arms for the management of patients with chronic respiratory disease. The models were implemented using Bayesian multilevel models, to reflect the hierarchical structure of the data while controlling for co-variates at the patient and country level. This analysis showed that directly modelling the level of HCRU is a promising approach to facilitate cost-effectiveness analyses conducted alongside multinational RCTs, offering several advantages compared with the modelling of direct costs. It is argued that modelling the level of HCRU within the Bayesian framework avoids confounding the price effects with the country effects and facilitates the estimation of costs for several countries represented in the trial.

Cancer Research and Privacy: The Problem With Being Joined at the Hip

Cancer Research and Privacy: The Problem With Being Joined at the Hip